Vascular endothelial dysfunction (ED) is a common effect of aging and is associated with many diseases including hypertension, coronary artery disease, stroke, cerebrovascular disease, peripheral vascular disease, diabetes, erectile dysfunction, atherosclerosis, asthma, rheumatoid arthritis, pulmonary hypertension, hyperhomocysteinemia, sickle cell disease, pre-eclampsia, chronic renal failure, sepsis, and multiple organ failure. The ability of tissues to repair themselves in response to injury or ischemia or to respond to therapeutic intervention appears to be greatly diminished because of ED.
Endothelial dysfunction may be due to decreased expression of nitric oxide synthase (NOS), altered activation of pathways that block intracellular signaling events, increased levels of endogenous NOS inhibitors such as asymmetric dimethylarginine (ADMA), increased degradation or conversion of NO to peroxynitrites (due to high levels of reactive oxygen species) or increased activity of arginase which converts L-arginine to urea, thereby limiting the availability of L-arginine as a substrate for NOS.
A number of recent studies indicate that arginase plays a key role in ED and the modulation of NOS activity by regulating intracellular L-arginine availability. In aging vessels with ED, for example, arginase is upregulated, but addition of a specific arginase inhibitor restores endothelial function and nitric oxide (NO) responsiveness of vessels. Other diseases where arginase inhibition overcoming ED has been shown include asthma, where increased arginase activity contributes to a deficiency of NO and decreased airway smooth muscle relaxation, pulmonary hypertension, and spontaneous and salt-induced hypertension. L-arginine supplementation has also been shown to reverse ED completely or partially in a pig model of hypertension, in dilation defects caused by ischemia/reperfusion, and has even been shown to improve walking capability in patients with peripheral arterial disease. These studies suggest a potential therapeutic role for drugs that decrease arginase upregulation or control the activity of arginase in a number of vascular diseases.
Recent studies have shown that both hypoxia and certain inflammatory mediators, including TNFα, increase arginase or decrease endothelial cell nitric oxide synthase (eNOS) activity. Both prolonged inflammation and chronic ischemia appear to contribute to ED.
There is a need for methods to treat endothelial dysfunction, which is responsible for, or contributes to, a great many diseases and disorders.